Comparison Between Dimethyl Fumarate, Fingolimod, and Ocrelizumab After Natalizumab Cessation
Authors: Chao Zhu, Tomas Kalincik, Dana Horakova, Zhen Zhou, Katherine Buzzard, Olga Skibina, Raed Alroughani, Guillermo Izquierdo, Sara Eichau, Jens Kuhle, Francesco Patti, Francois Grand’Maison, Suzanne Hodgkinson, Pierre Grammond, Jeannette Lechner-Scott, Ernest Butler, Alexandre Prat, Marc Girard, Pierre Duquette, Richard A. L. Macdonell, Bianca Weinstock-Guttman, Serkan Ozakbas, Mark Slee, Maria Jose Sa, Vincent Van Pesch, Michael Barnett, Bart Van Wijmeersch, Oliver Gerlach, Julie Prevost, Murat Terzi, Cavit Boz, Guy Laureys, Liesbeth Van Hijfte, Allan G. Kermode, Justin Garber, Bassem Yamout, Samia J. Khoury, Daniel Merlo, Mastura Monif, Vilija Jokubaitis, Anneke van der Walt, Helmut Butzkueven, Thomas P Leist, Lily  Habib, Paarami  Udugama, Orla  Gray, Dana  Horakova, Charlotte  Sartori, Rein  More, Ana  Siddiqui, Pamela  Farr, Dusko  Stupar, Cynthia  Tang, Alison  Le, Sonya  Smirnova, Gaurang  Palshetkar, Tim  Spelman
Journal: JAMA Neurology (2023)

Importance Natalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses. Objectives To compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab. Design, Setting, and Participants In this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023. Exposures Dimethyl fumarate, fingolimod, and ocrelizumab. Main Outcomes and Measures Primary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method. Results Among 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years; 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08); fingolimod, 0.26 (95% CI, 0.12-0.48); and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab. Conclusion and Relevance Study results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.